As processes for producing hinokitiol, the following processes have been known:
(i) a process in which hinokitiol is produced from methoxytropylidene via isopropyltropone and aminoisopropyltropone (Tetrahedron., 32, 1051 (1991)); PA1 (ii) a process in which hinokitiol is produced through 6 steps such as acetalization after epoxidation of carvone with hydrogen peroxide (JP-A-62-93250); PA1 (iii) a process in which hinokitiol is produced by converting isopropylcyclohexanone or isopropylcyclohexenone to cyanohydrin, and then synthesizing isopropylcycloheptanone through two steps, followed by oxidation, bromination and dehydrobromination (JP-A-63-5048 and JP-A-63-17841); and PA1 (iv) a process of reacting bromotropolone with an organotin compound, followed by reduction with hydrogen in the presence of Pd/C catalyst (J. Chem. Soc., Chem. Commun., 1989, 616 (1989)). PA1 (v) a process in which hinokitiol is produced by reacting cyclopentadiene with a Grignard reagent (ethylmagnesium bromide) and isopropyl tosylate to obtain 1-isopropylcyclopentadiene with high selectivity, adding a dichloroketene to the 1-isopropylcyclopentadiene, and subjecting the adduct to solvolysis (JP-B-51-33901); and PA1 (vii) a process of reacting cyclopentadiene with an aliphatic lower alcohol in the presence of a catalyst in a vapor phase (JP-B-4-27215) and a process of reacting cyclopentadiene with ethylene on a hydrocarbon in a vapor phase (Journal of Chemical Society of Japan, 1977 (3), p. 375 (1977)); PA1 (viii) a process of reacting cyclopentadiene with metallic sodium in liquid ammonia and then with an equal amount of an alkyl halide (Izv. Vyssh. Vchebn, Zaved., Khim. Khim. Technol., 19 (10), p. 1511 (1970)); PA1 (ix) a process of reacting cyclopentadiene with an alkyl halide in an aqueous metal hydroxide solution in the presence of a phase transfer catalyst such as a quaternary ammonium salt (U.S. Pat. No. 3,560,583) and a process of reacting cyclopentadiene with an alkali metal hydroxide in an organic solvent in the presence of a dehydrating agent such as calcium oxide to produce a cyclopentadienyl metal and reacting the cyclopentadienyl metal with an alkyl halide (Russian Patent No. 520341); PA1 (x) a process in which a Grignard reagent (an alkylmagnesium bromide) is used as in the above prior art (v) and a 1-alkylcyclopentadiene is selectively obtained by reacting a Grignard reagent of cyclopentadiene with an alkyl halide or an alkylsulfuric acid (Montasch. Chemie., 91, 805-812 (1960)); PA1 (xi) a process in which as the first step in the production process of a prostaglandin, the 1-isomer is produced by obtaining cyclopentadienyllithium from cyclopentadiene and an alkyllithium and reacting the cyclopentadienyllithium with ethyl 7-bromoheptanoate (JP-B-53-33583); PA1 (xii) a process in which the 1-isomer or 5-isomer is produced by obtaining a cyclopentadienyl metal solution from metallic sodium and cyclopentadiene in an organic solvent such as dimethoxyethane or diglyme and adding the solution dropwise to an alkylating agent (Tetrahedron, vol. 21, 2313 (1965)); PA1 (xiii) a process in which as the first step in the production process of a norbornene derivative, cyclopentadienylsodium is produced by reacting cyclopentadiene with sodium hydride in tetrahydrofuran solvent, and an alkylating agent is added dropwise to the cyclopentadienylsodium at a low temperature (described in the Referential Examples of JP-A-54-63063); and PA1 (xiv) a process in which as the first step in the production process of optically active cyclopentenediol, an alkylcyclopentadiene is obtained by reacting cyclopentadiene with an alkylating agent in the presence of a base (JP-A-6-239779). In this reference, substantially all kinds of alkylating agents are mentioned. As the base, there are mentioned a wide variety of alkali metals, alkaline earth metals, metal hydrides, alkali metal alkoxides, etc. As a solvent for the reaction, there are mentioned diethyl ether, n-hexane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. It is stated that any solvent may be used so long as it has no undesirable influence on the reaction, and solvents are mentioned with almost no restriction. However, in Examples, there is described only a case of reacting cyclopentadiene with sodium hydride in tetrahydrofuran solvent to produce cyclopentadienylsodium, and then adding an alkylating agent to the cyclopentadienylsodium. This process is exactly the same as the above prior art (xiii). PA1 a) a step of preparing a cyclopentadienyl metal from cyclopentadiene and at least one of a metal hydroxide or a metal alkoxide (preparation step of cyclopentadienyl metal); PA1 b) a step of obtaining isopropylcyclopentadiene by reacting the cyclopentadienyl metal with the isopropylating agent in the presence of an aprotic polar solvent capable of forming two liquid phases when mixed with isopropylcyclopentadiene as a product (isopropylation step); and PA1 c) a step of isomerizing 5-isopropylcyclopentadiene in the isopropylcyclopentadiene selectively to 1-isopropylcyclopentadiene with heat (isomerization step). PA1 mfd. by Wako Pure Chemical Industries, Ltd.; special grade.
These processes cannot be industrially practical because they comprise many steps or the starting materials are difficult to obtain.
As another production process, there is known a process of obtaining isopropylcyclopentadiene by the use of cyclopentadiene as a starting material, adding a dichloro-ketene to the isopropylcyclopentadiene, and subjecting the adduct to solvolysis. This process is industrially advantageous because the starting cyclopentadiene is easily available and the process comprises a small number of steps. It is known that in this process, hinokitiol is produced only from 1-isopropylcyclopentadiene among three isomers of isopropylcyclopentadiene. Therefore, investigations are conducted in order to increase the yield of the desired compound hinokitiol or reduce the troublesomeness of a purification step, by selectively synthesizing 1-isopropylcyclopentadiene. That is, the production of 1-isopropylcyclopentadiene with high selectivity is important in hinokitiol production.
As such a process, there are, for example, the following processes:
(vi) a process in which hinokitiol is produced by reacting cyclopentadiene with acetone under basic conditions to obtain 6,6-dimethylfulvene, reducing the 6,6-dimethylfulvene with a dialkylaluminum hydride to obtain 1-isopropylcyclopentadiene selectively, adding a dichloro-ketene to the 1-isopropylcyclopentadiene, and subjecting the adduct to solvolysis (JP-A-8-40971).
These processes are superior to the above processes (i) to (iv) because hinokitiol is obtained by fewer steps by using easily available and inexpensive cyclopentadiene as a starting material. But, they have the following defects: since a reagent requiring extreme nonaqueous conditions (i.e. the Grignard reagent in (v) or the dialkylaluminum hydride in (vi)) should be used, great precautions are necessary in handling the reagent; a solvent to be used and the like should be subjected to a special dehydration procedure; and these reagents are generally expensive. Thus, these processes for producing hinokitiol via 1-isopropylcyclopentadiene are also industrially disadvantageous.
The present inventors found that among isomers of isopropylcyclopentadiene, 5-isopropylcyclopentadiene is isomerized selectively to 1-isopropylcyclopentadiene by heat near room temperature. That is, the present inventors found that for hinokitiol production, it is important to synthesize 5- or 1-isopropylcyclopentadiene or a mixture thereof with high selectivity by the use of inexpensive and easily handleable reagents, while inhibiting the production of 2-isopropylcyclopentadiene as much as possible.
It is generally known that as described above, an alkylcyclopentadiene has three isomers 5-, 1- and 2-alkylcyclopentadienes due to the positions of the alkyl group. In a thermodynamically stable equilibrium state, an alkylcyclopentadiene is an isomer mixture consisting of substantially equal amounts of the 1-isomer and the 2-isomer and a small amount of the 5-isomer. ##STR1##
The following various processes for producing an alkylcyclopentadiene by alkylating cyclopentadiene have been known though they are not a process for producing hinokitiol:
The process (vii) has the following defects: a special apparatus for the vapor-phase reaction is necessary; the yield of the monoalkyl compound is low because of the production of substituted derivatives having two or more alkyl groups; and the alkylcyclopentadiene obtained is an equilibrium mixture, namely, the process does not give the 5-isomer or the 1-isomer selectively. The process (viii) is disadvantageous in that handling of the reagents used is difficult and that the alkylcyclopentadiene obtained is an equilibrium mixture. The process (ix) does not use a reagent requiring precautions in its handling, such as metallic sodium or liquid ammonia, but it gives only an alkylcyclopentadiene mixture having an equilibrium composition.
The processes (x) to (xii) give the 5-isomer and/or the 1-isomer with high selectivity. However, the process (x) and the process (xi) are difficult to practice industrially because an expensive reagent requiring extreme nonaqueous conditions should be used in both processes, namely, the Grignard reagent should be used in (x) as in (v) and the alkyllithium should be used in (xi). The process (xii) uses metallic sodium and hence requires extreme nonaqueous conditions. Moreover, the reference for the process (xii) describes only a case of adding a primary alkyl group. As a result of investigation by the present inventors, it has been found that the selectivity of the 5-isomer and/or the 1-isomer is low when a secondary or tertiary alkyl group having a low reactivity, such as an isopropyl group is added. Therefore, the process (xii) cannot be adopted in the process for producing hinokitiol of the present invention.
As to the process (xiii), in Reference Example 1, there is described in detail a process comprising cooling a tetrahydrofuran solution of cyclopentadienylsodium prepared from sodium hydride and cyclopentadiene to -45.degree. C. to -55.degree. C., adding thereto a primary alkyl bromide, and stirring the resulting mixture at the same temperature for 1 hour and then at -30.degree. C. to -45.degree. C. for 4.5 hours. In Reference Example 1, the proportions of the resulting isomers determined by the position of the alkyl group are not described but it is stated in the main text that in the alkylation carried out in the invention, the 5-isomer produced at first isomerizes to the 1-isomer and the 2-isomer immediately.
However, in Example 1 of the prior art (xiv), it is stated that a primary alkyl bromide is added dropwise to a tetrahydrofuran solution of cyclopentadienylsodium prepared from sodium hydride and cyclopentadiene, at -50.degree. C. This process is exactly the same as the process (xiii), but the 5-isomer is selectively obtained at a low temperature and the 1-isomer is selectively obtained by heating up to room temperature. There is no description about the production of the 2-isomer.
As described above, the description about the isomers in (xiii) is different from that in (xiv). As a result of investigation on Example of (xiv) by the present inventors, the products obtained by the reaction could not be identified as the isomers, respectively, by the .sup.1 H-NMR described in Example. Thus, it could not be confirmed that 5-alkylcyclopentadiene and/or 1-alkylcyclopentadiene can be obtained with high selectivity.
The process in Example of each of (xiii) and (xiv) uses sodium hydride. Since sodium hydride is a reagent which requires extreme nonaqueous conditions and is generally expensive, the process is very difficult to practice industrially. Investigation by the present inventors revealed that the addition of an isopropyl group as a secondary alkyl group according to this process gives only an isopropylcyclopentadiene mixture having such an equilibrium composition that the proportions of the 1-isomer and the 2-isomer is substantially equal. That is, the processes (xiii) and (xiv) cannot be applied to the production of hinokitiol.
As described above, there has been known no process for producing hinokitiol easily with high selectivity at low cost without extreme nonaqueous conditions.